THE ROLE OF STROMAL CELLS AND STROMAL-EPITHELIAL INTERACTION IN THE EARLY STAGES OF BREAST TUMOR PROGRESSION: IMPLICATIONS FOR RISK, PREVENTION AND TREATMENT The importance of stromal-epithelial interactions in established breast cancers has long been recognized, but the role of stromal cells in the early stages of breast cancer initiation and progression are much less well defined. It is possible that biological attributes of the normal stroma in many women may create conditions that favor the inception and progression of mammary carcinomas and/or that stromal cells may have distinct effects on the subsequent behavior of the epithelial cells that comprise pre-invasive lesions, such as epithelial hyperplasias and carcinomas in situ. A better understanding of the role of stromal cells in normal breast tissue from patients with and without breast cancer and a more complete appreciation of their role in precancerous breast lesions would not only help us understand the part these cells play in the early stages of breast tumorigenesis, but would also likely provide new molecular targets both for breast cancer treatment and prevention. The goals of this project, therefore, are to obtain a more complete understanding of the role of stromal cells and of stromal-epithelial interactions in the early stages of breast tumor initiation and progression. This project has three specific aims: Aim 1. To determine in human breast tissue samples if there is an association between expression of stromal markers that appear to have a role in established breast cancers with the presence of epithelial lesions known to be associated with increased breast cancer risk, and to determine if there are stromal markers that can be used as independent risk indicators in women with benign and pre-invasive breast lesions. Aim 2. To determine if stromal cells from uninvolved breast tissue from patients with breast cancer are more conducive to cancer development than stromal cells of women, without cancer and to determine the gene expression signatures of such stromal cells. Aim 3. To determine if targeting of genes and proteins involved in stromal-epithelial interactions could potentially be of therapeutic value.